PUBLICATION
Reduced U snRNP assembly causes motor axon degeneration in an animal model for spinal muscular atrophy
- Authors
- Winkler, C., Eggert, C., Gradl, D., Meister, G., Giegerich, M., Wedlich, D., Laggerbauer, B., and Fischer, U.
- ID
- ZDB-PUB-051012-2
- Date
- 2005
- Source
- Genes & Development 19(19): 2320-2330 (Journal)
- Registered Authors
- Winkler, Christoph
- Keywords
- Survival motor neurons (SMN), U snRNP assembly, motoneuron, spinal muscular atrophy, zebrafish
- MeSH Terms
-
- Animals
- Axons/metabolism
- Axons/pathology
- Disease Models, Animal
- Embryo, Nonmammalian/embryology
- Embryo, Nonmammalian/pathology
- Fibroblasts/metabolism
- HeLa Cells
- Humans
- Muscular Atrophy, Spinal/genetics
- Muscular Atrophy, Spinal/metabolism*
- Muscular Atrophy, Spinal/pathology
- Nerve Tissue Proteins/genetics
- Nerve Tissue Proteins/metabolism*
- RNA Interference*
- RNA-Binding Proteins
- Ribonucleoproteins, Small Nuclear/genetics
- Ribonucleoproteins, Small Nuclear/metabolism*
- Xenopus laevis
- Zebrafish/embryology*
- Zebrafish/genetics
- PubMed
- 16204184 Full text @ Genes & Dev.
Citation
Winkler, C., Eggert, C., Gradl, D., Meister, G., Giegerich, M., Wedlich, D., Laggerbauer, B., and Fischer, U. (2005) Reduced U snRNP assembly causes motor axon degeneration in an animal model for spinal muscular atrophy. Genes & Development. 19(19):2320-2330.
Abstract
Spinal muscular atrophy (SMA) is a motoneuron disease caused by reduced levels of survival motoneuron (SMN) protein. Previous studies have assigned SMN to uridine-rich small nuclear ribonucleoprotein particle (U snRNP) assembly, splicing, transcription, and RNA localization. Here, we have used gene silencing to assess the effect of SMN protein deficiency on U snRNP metabolism in living cells and organisms. In HeLa cells, we show that reduction of SMN to levels found in SMA patients impairs U snRNP assembly. In line with this, induced silencing of SMN expression in Xenopus laevis or zebrafish arrested embryonic development. Under less severe knock-down conditions, zebrafish embryos proceeded through development yet exhibited dramatic SMA-like motor axon degeneration. The same was observed after silencing two other essential factors in the U snRNP assembly pathway, Gemin2 and pICln. Importantly, the injection of purified U snRNPs into either SMN- or Gemin2-deficient embryos of Xenopus and zebrafish prevented developmental arrest and motoneuron degeneration, respectively. These findings suggest that motoneuron degeneration in SMA patients is a direct consequence of impaired production of U snRNPs.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping